Hemoglobin S polymerization is the primary determinant of the abnormal rheology associated with sickle cell anemia, which is characterized by chronic hemolysis and acute painful crises. Measurements of abnormal cell rheology in sickle cell anemia continue to provide correlations with clinical manifestations although the detailed mechanisms leading to such clinical endpoints are not well understood. The profound effect of hemoglobin S polymerization on cell rheology has given rise to a variety of therapeutic strategies designed to reduce the extent of intracellular polymerization. We have examined the solubility of hemoglobin S mixtures with hemoglobins A, A2 and F at varying oxygen saturations to determine the extent of hemoglobin S polymerization under physiologic conditions. A detailed analysis provides the means to predict the maximum extent of polymerization within the sickle hemoglobin containing erythrocyte. Equilibrium solubility of sickle hemoglobin mixtures confirm previous findings that the sparing effect on hemoglobin S polymerization of hemoglobin F is greater than the sparing effect of hemoglobin A in mixtures of hemoglobin S. The current study also demonstrates explicitly the polymerization behavior of hemoglobin S and hemoglobin F mixtures at increasing ligand concentrations. The theoretical model based on experimental data of polymerization of hemoglobin mixtures was used to analyze data obtained from the Parisian Prospective Study on Sickle Cell Disease in children with sickle cell anemia during the first two years of life. These data indicated that 3 of 21 children had a significantly greater predicted polymerization tendency due to early decreases in hemoglobin F. These individuals will be studied prospectively to ascertain the relationship among polymerization tendency and various clinical manifestations of sickle cell disease. Observations obtained from 2674 individuals with sickle cell anemia from the Cooperative Study of Sickle Cell Disease database indicated that changes in red cell indices result in continuous rise in polymerization tendency during the first twelve years of life.